Endoglin, a TGF-β binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1

@article{McAllister1994EndoglinAT,
  title={Endoglin, a TGF-$\beta$ binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1},
  author={Kimberly A McAllister and Kenny Grogg and D. W. Johnson and Carol J. Gallione and Marjorie A. Baldwin and Charles E. Jackson and Elizabeth A. Helmbold and Dorene Markel and Wendy C. McKinnon and J. Colin Murrel and Mary Kay McCormick and Margaret A. Pericak-Vance and Peter Heutink and Ben A. Oostra and Tjeerd Haitjema and C J Westerman and Mary E.M. Porteous and Alan Guttmacher and Michelle Letarte and Douglas A. Marchuk},
  journal={Nature Genetics},
  year={1994},
  volume={8},
  pages={345-351}
}
Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterized by multisystemic vascular dysplasia and recurrent haemorrhage. Linkage for some families has been established to chromosome 9q33–q34. In the present study, endoglin, a transforming growth factor β (TGF-β) binding protein, was analysed as a candidate gene for the disorder based on chromosomal location, expression pattern and function. We have identified mutations in three affected individuals: a C to G… 

Cloning of the Promoter Region of Human Endoglin, the Target Gene for Hereditary Hemorrhagic Telangiectasia Type 1

Theendoglin promoter exhibited inducibility in the presence of TGF-β1, suggesting possible therapeutic treatments in HHT1 patients, in which the expression level of the normal endoglin allele might not reach the threshold required for its function.

Cloning of the promoter region of human endoglin, the target gene for hereditary hemorrhagic telangiectasia type 1.

The endoglin promoter exhibited inducibility in the presence of TGF-beta1, suggesting possible therapeutic treatments in HHT1 patients, in which the expression level of the normal endogli allele might not reach the threshold required for its function.

Mutations in endoglin and in activin receptor‐like kinase 1 among Danish patients with hereditary haemorrhagic telangiectasia

A denaturating gradient gel electrophoresis protocol for mutation scanning of the two loci of HHT proved to be very sensitive for mutation detection in both ENG and ALK1.

Mutations in the activin receptor–like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2

A new 4 cM interval for ORW2 is reported that does not overlap with any previously defined and suggests a critical role for ALK1 in the control of blood vessel development or repair.

The activin receptor-like kinase 1 gene: genomic structure and mutations in hereditary hemorrhagic telangiectasia type 2.

The high rate of detection of mutations by genomic sequencing of ALK-1 suggests that this will be a useful diagnostic test for HHT2, particularly where preliminary linkage to chromosome 12q13 can be established.

Three novel mutations in the activin receptor-like kinase 1 (ALK-1) gene in hereditary hemorrhagic telangiectasia type 2 in Brazilian patients

The high rate of mutation detection and the small size of the ALK-1 gene make genomic sequencing a viable diagnostic test for HHT2, and data indicate that loss-of-function mutations in a single allele of theALK1 locus are sufficient to contribute to defects in maintaining endothelial integrity.

Mutation and expression analysis of the endoglin gene in hereditary hemorrhagic telangiectasia reveals null alleles

11 novel ENG mutations in HHT kindreds are described, which include missense and splice‐site mutations, which suggest that the nature of most ENG mutations is to create a null (nonfunctional) allele, and that there is no requirement for the synthesis of a truncated endoglin protein in the pathogenesis of HHT.

Mutant endoglin in hereditary hemorrhagic telangiectasia type 1 is transiently expressed intracellularly and is not a dominant negative.

Results indicate that mutated forms of endoglin are transiently expressed intracellularly and not likely to act as dominant negative proteins, as proposed previously.

Mutation affecting the proximal promoter of Endoglin as the origin of hereditary hemorrhagic telangiectasia type 1

The novel ENG c.-58G > A substitution in the ENG promoter co-segregates with HHT symptoms in a family and appears to affect the transcriptional regulation of the gene, resulting in reduced ENG expression.

Involvement of the TGF-β superfamily signalling pathway in hereditary haemorrhagic telangiectasia

The underlying molecular and cellular bases and the therapeutic approaches that have been addressed in the laboratory in recent years are reviewed.
...

References

SHOWING 1-10 OF 34 REFERENCES

Assignment of the human endoglin gene (END) to 9q34-->qter.

The localization of the human endoglin gene (END) to human chromosome 9 is reported on, by Southern blot analysis of BglII fragments of DNA from human-hamster somatic cell hybrids, indicating a telomeric position with respect to the Philadelphia breakpoint.

A disease locus for hereditary haemorrhagic telangiectasia maps to chromosome 9q33–34

This work has mapped the HHT gene, by linkage analysis, to markers on 9q33–34 in two large multi–generation families and provides a starting point for the eventual cloning of the gene.

A gene for hereditary haemorrhagic telangiectasia maps to chromosome 9q3

It is concluded that HHT is a genetically heterogeneous disorder and based on its map location (9q3) and expression in vascular tissues, type V collagen is a possible candidate gene for HHT.

Molecular characterization and in situ localization of murine endoglin reveal that it is a transforming growth factor-beta binding protein of endothelial and stromal cells.

Murine fibroblast endoglin is capable of binding TGF beta 1 and the stromal cells in the connective tissue of intestine, stomach, heart, muscle, uterus, ovary, and testis were strongly and specifically reactive with complementary RNA probes and with a polyclonal antibody toendoglin; epithelial cell layers were distinctly unreactive.

Identification and expression of two forms of the human transforming growth factor‐β‐binding protein endoglin with distinct cytoplasmic regions

Both forms were shown to bind TGF‐β1 and, when overexpressed in transfected mouse fibroblasts, to form disulfide‐linked homodimers, indicating that the cysteine residues present in the extracellular domain are responsible for the dimerization.

Targeted disruption of the mouse transforming growth factor-β1 gene results in multifocal inflammatory disease

TGF-β1-deficient mice may be valuable models for human immune and inflammatory disorders, including autoimmune diseases, transplant rejection and graft versus host reactions.

Transforming growth factor receptor gene TGFBR2 maps to human chromosome band 3p22.

The chromosomal position of the gene that encodes the type II receptor of TGF-beta (HGM symbol TGFBR2), a multifunctional regulator of cell proliferation and differentiation, is mapped to 3p22.

Linkage of hereditary haemorrhagic telangiectasia to chromosome 9q34 and evidence for locus heterogeneity.

It is concluded that HHT is a genetically heterogeneous disorder and the results indicate that the presence of PAVM may be more common in patients with a chromosome 9 linked form of HHT than in Patients with the non-linked form.